Aplasia/Agenesis and Related Aberrancy of Salivary Glands

Congenital aplasia or agenesis of the major salivary glands is an uncommon finding, characterized by partial or total lack of development of the gland. Agenesis may involve one gland, pairs, or multiple glands, and be unilateral or bilateral. It may be a single independent finding or be associated with other developmental anomalies.

Congenital agenesis of major salivary glands was first reported by Gruber in 1985. A recent search of the world literature reported 30 documented cases. Three cases of unilateral aplasia of the parotid have been reported. As it may be asymptomatic and go unnoticed, the true incidence is unknown. Bilateral agenesis is more common, with 10 cases reported in the English literature. Sometimes congenital absence of one parotid or submandibular gland is associated with hypertrophy of the contralateral gland.

Aplasia may occur as a single event or with autosomal dominant inherited developmental conditions such as first branchial arch anomalies, hemifacial microsomia and mandibulofacial dysostosis. Parotid gland aplasia may be associated with malformations of the lacrimal apparatus as well. A combination of multiple developmental anomalies is found in the lacrimo-auriculo-dento-digital (LADD) syndrome (Levy–Hollister syndrome). This is an autosomal-dominant multiple congenital anomaly disorder characterized by hypoplasia, aplasia or atresia of the lacrimal and salivary systems, ear anomalies, hearing loss, digital malformations and dental alterations. As the parotid gland develops during the 4th week of uterine life, and the submandibular and sublingual, and minor glands develop between 6th and 12th weeks, association of salivary gland aplasia with other congenital abnormalities is easily understood. Bilateral aplasia of the parotid gland has also been reported in a patient with Down’s syndrome. In ectodermal dysplasia, aplasia of the submandibular glands and alterations in salivary gland function have been reported as well.

Hyperplasia of Minor Salivary Glands

Saliva

Saliva is an essential fluid for maintaining oral and systemic health and a satisfactory quality of life. While saliva is sometimes considered bothersome during restorative procedures, the alteration in quality and/or quantity of saliva has serious sequelae for the patient. Saliva is the product of three paired major salivary glands (the parotid, submandibular, and sublingual), and minor glands found in the hard and soft palate, lips, tongue, and buccal mucosa (Figure 1). Major salivary glands are composed of ductal and acinar structures. The acinar cells are the secretory components and ductal cells are the branching network that transports saliva into the oral cavity. The acinar cells of the parotid gland are purely serous elements and upon stimulation, parotid secretions account for at least half of the volume of whole saliva. Serous secretions are ‘watery’ and contain digestive enzymes, water, salts, and ions. They aid in mastication, clearing agents from the oral cavity, and facilitate swallowing and speech. Fluid from the parotid gland enters the oral cavity through the main excretory duct, Stensen’s duct, located in the buccal mucosa next to the maxillary second molars. In the submandibular gland, the acinar components are mixed mucous-serous, but predominantly serous. At rest, the submandibular gland secretions account for approximately two-thirds of the unstimulated saliva production. Wharton’s duct is the main duct of the submandibular gland and enters the floor of the mouth on either side of the lingual frenum. The sublingual gland, the smallest of the three major glands, is located above the mylohyoid muscle. Acinar elements are mixed, but predominantly mucous. The mucin produced facilitates lubrication and swallowing. The main excretory duct of the sublingual gland, Bartholin’s duct, may join Wharton’s duct resulting in a blending of secretions, or open into the oral cavity with a separate sublingual papilla. Numerous sublingual ducts may join the submandibular gland duct or open separately into the floor of the mouth. Minor salivary glands are named according to their location—lingual (anterior and posterior), labial, buccal, palatine and glossopalatine. Table 1 summarizes the nomenclature for the major and minor salivary glands and their acinar components.

In health, approximately 750 ml of saliva is produced in a day. The principal control of salivary secretion is mediated by sympathetic and parasympathetic innervation. The adrenergic (α and β) receptors are regulated by the sympathetic nervous system and the muscarinic receptors by the parasympathetic nervous system. At least five muscarinic-cholinergic receptor subtypes exist and it has been determined that the muscarinic receptor that medicates secretion of saliva is the M3 subtype. The parasympathetic nerve stimulation leads to an increased volume of saliva, whereas the sympathetic stimulation has an effect on protein content and salivary composition.

Saliva plays a major role in the local and systemic protection of the oral cavity, oropharyngeal region, and the upper gastrointestinal tract. Normal quantity and protein composition is essential for buffering the acidity of the oral cavity, lubrication of tissues, maintaining the integrity of the oral tissues, providing antimicrobial proteins and digestive enzymes, and remineralization of the teeth. Lack of saliva, hyposalivation, may increase a patient’s susceptibility to dental decay, oral ulcers, fungal infections, and dysphagia or difficulty in swallowing.

Saliva contains many antimicrobial proteins that help maintain a normal oral flora. The histatins provide antifungal properties, and proline-rich proteins help reduce bacterial colonization by modifying the ability of organisms to attach to tissues. Mucins are salivary glycoproteins that play a role in mucosal lubrication and assist in aggregation of oral microorganisms. Statherin and proline-rich proteins have calcium-binding properties to assist remineralization. These proteins combined with the cleansing and flushing ability of saliva constitute significant protective mechanisms for the oral cavity and upper gastrointestinal system. Of special importance to the dentition is the presence of buffers to help maintain a neutral pH and the remineralizing capacity. The pH range of saliva will vary from 6.7 to 7.4 in health. Of concern is pH below 5.5, which will promote enamel dissolution and increase caries susceptibility.

Hypofunction and Xerostomia

Altered saliva production, both qualitatively and quantitatively, creates significant oral health concerns for the patient and challenges the dentist to provide appropriate patient education and treatment. Patients frequently present with the complaint of a ‘dry mouth’. Xerostomia is the subjective sensation of dry mouth and may be determined by questioning individuals about their perceptions of oral dryness. The need to sip water while eating dry foods, difficulty in swallowing food without liquids, and a feeling of ‘too little’ saliva in the mouth have been correlated with salivary gland hypofunction. Hyposalivation is the production of inadequate or less than normal amount of saliva, usually from gland hypofunction. A few simple chairside assessments could be performed to quickly assess oral dryness. The lack of salivary pooling in the floor of the mouth is a basic clinical indicator of hyposalivation. Another indicator is the ‘cracker sign’. If a patient states that they cannot eat a cracker without drinking fluids, xerostomia and hyposalivation should be suspected. Another indicator is the ‘lipstick sign’. Patients with hyposalivation may have lipstick adhere to the incisal edges of the anterior teeth because they lack saliva that would normally prevent adherence. Another clinical clue to hypofunction is the ‘mouth mirror test’. The clinician places the mirrored surface of the mouth mirror over the buccal mucosa and attempts to move it. If the mirror glides effortlessly over the tissue, one can deduce that salivation is adequate.

The prevalence of xerostomia in the population varies widely due to the lack of a clear definition for xerostomia. Some clinicians use the terms ‘xerostomia’ and ‘hyposalivation’ interchangeably. Hyposalivation or salivary gland hypofunction results when the salivary gland flow rate is lower than normal. Defining ‘normal’ is problematic due to variations in the literature on collection methods, time of day collections were performed, and the inability to control for medications. Unstimulated whole salivary flow rates of less than 0.15 ml/min might provide a good reference for hyposalivation. The determination of hyposalivation and xerostomia do not consistently correlate as one might expect. Patients with salivary gland hypofunction are sometimes without complaints of oral dryness, or xerostomia. Conversely, patients with complaints of ‘dry mouth’ may not have reduced salivary flow rates. Xerostomia and salivary hypofunction affect the oral health-related quality of life. Reported reasons include the negative impact of oral dryness on speaking, eating, and wearing dental prostheses. Both xerostomia and salivary gland hypofunction require a careful systematic evaluation to determine causative factors.

Dry mouth has a variety of causes as indicated in Box 1. Common causes of salivary gland dysfunction leading to hyposalivation include medications, irradiation to the head and neck, and autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjogren’s syndrome (SS). Other systemic conditions affecting salivary glands include sarcoidosis, sialadenosis, and viral infections such as HIV and hepatitis C.

Mouth-breathing, tobacco smoking, alcohol use, and consumption of beverages containing caffeine can contribute to oral dryness as well. Age-related hyposalivation has been reported due to structural changes in salivary glands with increasing age. Other studies have reported no age-dependent decrease in saliva flow rate in healthy elderly populations. The incidence of xerostomia will increase and the oral manifestations will continue to be a challenge for the clinician.

Treatment of xerostomia is symptomatic and supportive, but should be aggressively proactive in prevention of dental decay associated with salivary hypofunction. Patient education and patient empowerment so they become participants in their oral healthcare are key to successful outcomes. Hydration, dietary modifications and meticulous oral hygiene are especially helpful. Symptomatic treatment is aimed at minimizing the subjective complaints, and includes drinking water or finely crushed ice chips and sugar-free fluids. Patients should be advised that caffeine can contribute to the feeling of oral dryness and consequently, caffeine-free and sugar-free drinks should be strongly encouraged. Avoiding alcohol, including alcohol-based mouthrinses, spicy foods, and strong flavorings, such as cinnamon and mint, should also minimize oral discomfort. Artificial saliva is helpful for many patients due to the coating action, but does not provide long-lasting relief. Some patients find relief by chewing sugar-free gum or sucking on sugar-free candies. Lip balms and moisturizers may be helpful as well.

Because patients with hyposalivation are at increased risk for dental decay, oral applications of topical fluorides should be initiated. The fluoride is incorporated into the enamel of the teeth to increase resistance to demineralization and decay. Fluoride products are available over-the-counter as rinses and as more highly concentrated brush-on gels (0.4% stannous fluoride gel). Prescription products are available which provide 1.1% neutral sodium fluoride treatment in convenient brush-on gels or rinses. These should be used after regular toothbrushing in the evening just before retiring. Patients should be reminded to avoid rinsing, eating or drinking for 30 minutes following the fluoride application. Stannous fluoride or neutral sodium fluoride treatments can be provided using fluoride carriers, or custom trays fabricated from a cast of the patient’s mouth. The carriers are particularly helpful in treating severe hyposalivation resulting from head and neck radiation therapy. Preventive fluoride programs should be customized by the dentist to meet the specific needs and conditions of the patient.

Xerostomia and Salivary Gland Hypofunction due to Medications

Jacobsen and Chavez in their article describe that individual above 65 years of age comprise 13% of the population, but consume approximately one-third of all drugs prescribed. Loesche et al and Foc have reported many studies that have demonstrated a link between dry mouth in the elderly and polypharmacy. Shinkai et al reported that in a group of 1,163 adults (age range 32–81 years), 57% reported dry mouth to be the most frequent side effect of their medications. Hundreds of medications can cause subjective complaints of dry mouth and many induce hyposalivation. The drugs most frequently implicated in dry mouth include the tricyclic antidepressants, antipsychotics, atropinics, beta blockers and antihistamines. In another study as reported by Thomson, the unstimulated (resting) salivary flow rate was reduced among individuals who were older, female, or taking antidepressants, and higher among smokers or people who were taking hypolipidemic drugs. Other studies have correlated dry mouth with the number of medications taken, rather than specific types of medications. Field et al have demonstrated that medication is a better predictor of risk status for dry mouth than either age or gender. Medications that induce salivary hypofunction are a concern among the elderly, but xerostomia can also be a concern for young adults. Thomson et al in his study involving a large cohort of 32-year-old subjects, reported that the prevalence of xerostomia was found to be 10%, with no apparent gender difference. There was a strong association between xerostomia and diminished oral health-related quality of life. Xerostomia was significantly higher among those taking antidepressants, iron supplements, or narcotic analgesics, and those subjects taking antidepressants at both 26 and 32 years of age demonstrated 22 times the odds of reporting xerostomia.

A study of medications and caries among older individuals by Thomson et al revealed that an adjusted coronal caries increment (AdjCI) was higher among males and those taking a beta blocker or an anti-asthma drug for the previous 5 years. Several classes of drugs have been associated with dry mouth (Box 2). The most common groups include those with: (i) anticholinergic effects such as tricyclic antidepressants, drugs for urinary retention and over-active bladder, antipsychotics, diuretics, and antihistamines; (ii) sympathomimetic drugs such as antihypertensives, anti-depressants, decongestants, and bronchodilators; (iii) skeletal muscle relaxants; (iv) benzodiazepines; (v) proton pump inhibitors; and (vi) anti-migraine agents. Dry mouth has been reported to be a consequence of cytotoxic drugs such as 5-fluorouracil. Medications used for treatment of HIV have also been associated with dry mouth. These include didanosine and protease inhibitors.

It is important for the dentist to inquire about all medications, both prescription and over-the-counter agents, during the health history review. Sometimes the dentist can provide assistance by sharing concerns of medication-induced hyposalivation with the primary care physician. In some situations, the dentist might suggest medications such as pilocarpine or cevimeline to promote salivation. These medications will be discussed in the section on Sjögren’s syndrome.

Xerostomia and Salivary Gland Hypofunction due to Radiation Therapy

The role of saliva in oral health and function relates both to its fluid characteristics and to its specific components. The water (fluid) phase accounts for 99% of the volume and the remainder is salts and proteins. Essential functions of these components include flushing, buffering the acidity, and mucosal coating to maintain tissue integrity. Mucosal coating and tissue lubrication are essential for speech, taste perception, mastication, and swallowing. Cancer patients undergoing treatment for head and neck disease often experience severe difficulties maintaining such functions. Salivary function can also be diminished by radioiodine therapy for thyroid carcinoma, especially if multiple doses are administered. Deterioration of oral health and radiation-induced oral dryness has a significant influence on patients’ overall quality of life during and after treatment.

Together with surgery, radiation therapy is the main treatment for head and neck tumors. All or part of the major and minor salivary glands may be included within the radiation field due to the site and extension of the tumor and the lymphatic spread. Exposing the glands to radiation often results in severe salivary gland hypofunction and changes in saliva composition. A profound decrease in salivary flow occurs during the 1st week of radiation therapy and continues throughout the course of therapy. In general, fully irradiated parotid glands exposed to doses exceeding 60 Gy sustain permanent damage resulting in severe hypofunction, and there is no recovery of gland function over time. Partial salivary flow recovery may occur at lower doses.

Radiation mucositis may begin during the 2nd week of therapy. Primary sites are intraoral mucosal surfaces within the direct portals of radiation. A whitish discoloration will appear from keratin accumulation, which is followed by sloughing, revealing atrophic erythematous, and friable mucosa. Ulceration then develops producing burning and pain which is exacerbated by eating and oral hygiene. Symptomatic support for radiation mucositis is important to assist the patient in maintaining adequate nutrition.

The mucositis will slowly resolve 2–3 weeks after cessation of the treatment. A loss of taste has been reported which generally is recovered after 6 months.

Minimizing the probability of osteoradionecrosis (ORN) includes a dental examination at least 2 weeks prior to the initiation of radiation therapy to address or remove teeth that have a hopeless long-term prognosis. Daily fluoride treatments in custom carriers and close follow-up aid in reducing the incidence of xerostomia-induced dental caries. Due in part to more efficient radiation techniques, the incidence of ORN has been declining in radiation patients over the last two decades. Advances in radiation techniques, including the use of fractionated radiation doses, have minimized the incidental damage to adjacent tissues. Furthermore, use of three-dimensional dosimetric intensity-modulated radiation therapy (IMRT) has been shown to reduce late salivary toxicity, since the portion of tissue exposed to low radiation doses has a potential for repair. Based on recent publications, the prevention of ORN remains controversial. A recent report compiled by Chang et al after reviewing a large series of ORN studies stated that extraction of teeth with poor prognosis before radiation therapy did not appear to reduce the risk of ORN. The investigation of IMRT by Wu et al to achieve sparing of the parotids and yet achieve higher tumor control appears to show promise. Until additional evidence is available to define guidelines, a pre-radiation referral for a dental evaluation is necessary. To facilitate prevention of ORN, irradiated dental patients should maintain a high level of oral health. Pre – and post-therapy close collaboration by a multidisciplinary team can be invaluable for patients receiving head and neck radiation therapy.

Sjögren’s Syndrome

Sjögren’s syndrome (SS) is a chronic autoimmune disease affecting the exocrine glands, primarily the salivary and lacrimal glands. Patients most commonly complain of a subjective persistent feeling of dry mouth (xerostomia) and of dry eyes (keratoconjunctivitis sicca). This is due to lymphocytic infiltrates and destruction of salivary and lacrimal glands and systemic production of autoantibodies. In 1933, Henrik Sjögren, a Swedish ophthalmologist, presented his doctoral thesis entitled ‘Zur Kenntnis der Keratoconjunctivitis Sicca’, and described the clinical and histopathological aspects of the disease.

Sjögren’s syndrome occurs worldwide and while it may occur at any age, the peak incidence is between 40 and 50 years. Sjögren’s syndrome has one of the highest female-to-male ratio (9:1) of any autoimmune rheumatic disease. In addition to ocular and oral dryness, a wide spectrum of extraglandular manifestations may occur as well. The musculoskeletal, hematological, vascular, pulmonary, gastrointestinal, dermatological, renal and nervous systems may be involved. Patients with SS have an increased risk of developing lymphoma. Early reports estimated that patients with SS had up to 44 times increased risk of developing lymphoma compared with the general population. Chronic fatigue, depression, and a diminished quality of life are also common components of SS.